Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by recurrent arterial and/or venous thrombosis and pregnancy morbidities in the persistent presence of autoantibodies against phospholipid binding proteins (aPL). The syndrome occurs either as primary or secondary disorder to other autoimmune diseases such as systemic lupus erythematosus. APS has a strong social and economical impact affecting mainly young people and inducing disability as a consequence of stroke or myocardial infarction1. A few patients manifest a life-threatening form of APS characterized by thrombotic occlusion of small vessels in different organs developing in a short period of time and leading to multi-organ failure2. Pregnancy morbidity includes recurrent early and late miscarriages, intrauterine growth restriction, prematurity, and pre-eclampsia with high social and economical costs1,3.
Data obtained from clinical studies and animal models argue for the involvement of antibodies in thrombus formation and miscarriage in APS. Although several PL-binding proteins have been identified as potential targets of aPL, there is strong evidence that β2-glycoprotein I (β2GPI) is the most relevant target antigen4-7.
We have recently reported a significant increase in fetal loss in pregnant mice immunized with human β2GPI following injection of fluorescent-labeled purified protein that binds selectively at fetal implantation sites8. We also found that removal of antibodies to β2GPI from aPL-IgG purified from APS patients by affinity chromatography significantly reduced their thrombotic effect in the rat mesenteric microcirculation9.
Although antibodies display a modest reactivity with the molecule in the fluid phase, it is widely accepted that they bind preferentially to β2GPI present on the membrane of different cell types including endothelial cells, platelets, monocytes and trophoblast plays a major pathogenic role10. In particular, pathogenic aPL have recently been suggested to recognize an conformational immunodominant epitope formed in Domain I (DI) of β2GPI7. The mechanisms linking aPL to blood clotting and fetal loss encompass inhibition of natural anticoagulants and fibrinolysis, activation of endothelial cells, platelets and monocytes resulting in expression of adhesion molecules and release of tissue factor, inhibition of syncytium-trophoblast differentiation and promotion of decidual inflammation10. However, these aPL-mediated effects have been proposed mainly on the basis of in vitro data, but the in vivo relevance of these observations remains to be fully established.
Compelling evidence for the critical role played by complement in APS has been obtained in animal models starting from the finding by Holers and colleagues11 that mice deficient in C3 or treated with an inhibitor of the C3 convertase are protected from aPL-mediated fetal resorption and growth retardation. Subsequent studies led to the identification of the activation products of the terminal pathway C5a and MAC as mediators of fetal loss and thrombus formation using animals with selective complement deficiencies or treated with specific inhibitors12. Although most of these observations were made with aPL of undefined specificity, the role of complement in inducing aPL-mediated blood clotting and fetal resorption has also been confirmed using specific antibodies to β2GPI8,9.
In recent years major efforts have been made to control the pathologic effects of aPL preventing the development of thrombi and miscarriages. Anticoagulants such as heparin or warfarin are currently used to prevent vascular thrombi and the combination of low-dose aspirin and low molecular weight heparin represents the first-line treatment for obstetric complications of APS. However, despite the success of these therapeutic approaches in several patients with APS, there is still a good proportion of patients varying between 20 and 30% who do no benefit from these treatments13-14,15.